In 1958, Verner and Morrison (280) first described refractory watery diarrhea and hypokalemia associated with noninsulin-secreting tumors of the pancreatic islets. The absence of gastric hypersecretion and even achlorhydria were documented in patients with this tumor syndrome,(280-282) later termed pancreatic cholera because the observed severe diarrhea resembled Vibrio cholerae disease (283). The acronym WDHA (watery diarrhea [100%], hypokalemia [100%], achlorhydria)(284) was proposed, although a more appropriate acronym might be WDHHA, for watery diarrhea hypokalemia, hypochlorhydria, and acidosis, because of bicarbonate wasting. Several reported series have confirmed the association between certain pancreatic tumors and watery diarrhea syndrome (274;285;286).

In a review of 55 patients with the diarrhea and hypokalemia syndrome, other features were sometimes observed: alkalosis in mild cases but acidosis in severe diarrhea from bicarbonate wasting, flushing, hypercalcemia, tetany (perhaps from magnesium depletion), abnormal glucose tolerance, and dilation of the gallbladder (286). The most prominent symptom in most patients is profuse cholera-like diarrhea, which often is present for 3 or 4 years before diagnosis, with volumes usually exceeding 6 to 8 L of stool every 24 hours. Stool has the appearance of dilute tea and is rich in electrolytes, with an average secretion of 300 mmol of potassium per 24 hours. The diarrhea always is secretory in nature, will not disappear with fasting for 48 hours, and demonstrates an increased net secretion of electrolytes in the stool. This symptom may be confused with the diarrhea found in the Zollinger-Ellison syndrome; the distinguishing features are shown in Table 8.

Diarrhea that is not secretory always results from causes other than endocrine tumors. Laxative abuse may be very difficult to exclude, however, and the measurement of stool electrolytes and osmolarity may be required. Stool electrolytes should account for the osmolarity if the condition results from an endocrine tumor. An osmolarity exceeding that expected from the concentration of electrolytes invariably reflects laxative abuse, which must be carefully excluded.

The episodic and fulminating, secretory diarrhea associated with VIPomas results in profound hypokalemia, hypochlorhydria (rarely achlorhydria), bicarbonate wasting, and hyperchloremic metabolic acidosis. The more commonly observed hypochlorhydria results from the direct gastric acid inhibitory effect of VIP, a biologic property that is shared with other members of the secretin-glucagon family: secretin, glucagon, gastric inhibitory peptide (GIP), and polypeptide histidine and isoleucine (287). In the early stage of tumor growth, the predominant symptoms of diarrhea are episodic and intermittent. It generally is accepted that as the VIP tumor enlarges, the diarrhea becomes continuous and the ensuing electrolyte abnormalities life-threatening (274;285). Increased intestinal motility as well as secretion may contribute to the diarrhea (224).

The clinical features of VIPomas are consistent with the known actions of VIP, which include stimulation of intestinal secretion, facial flushing, inhibition of gastric acid secretion, stimulation of glycogenolysis, and hypercalcemia (285;286;288-292). The structural homology between VIP and secretin, glucagon, GIP, and peptide histidine and isoleucine (291) may account for enhanced secretion of pancreatic juice and inhibition of gastric acid secretion. VIP also has been reported to cause gallbladder relaxation; a large distended gallbladder often is found in patients with the VIPoma syndrome. Hypercalcemia has been noted in nearly 50% of patients with the syndrome. The cause is not clear, but it may relate to dehydration, electrolyte disturbances secondary to diarrhea, coincidental MEN accompanied by hyperparathyroidism, or secretion by the tumor of a calcitrophic peptide. Tetany has been reported in several patients and may result from hypomagnesemia secondary to the diarrhea. Nearly 8% of patients demonstrate facial flushing. The cause of this patchy erythematous and, sometimes urticarial, flushing is not clear, but it has been attributed to VIP or prostaglandins, which may be present in the tumor. The hyperglycemia often noted in patients with the watery diarrhea syndrome probably is secondary to the profound glycogenolytic effect of high portal vein VIP on the liver(290).

Sites of Tumors Secreting VIP

Tumors secreting VIP usually originate in the pancreas or along the sympathetic chain. In a series of 62 patients, 52 (84%) had pancreatic tumors and 10 (16%) had ganglioneuroblastomas (293). Of the 10 patients with ganglioneuroblastomas, 7 were children.

There have been 18 other case reports of elevated plasma levels of VIP that have been associated with neurogenic tumors, including ganglioneuroblastoma, ganglioneuromas, neurofibroma, and pheochromocytoma (294-303). Primary VIPomas now have been reported in other sites as well, including colon, lung, esophagus, jejunum, and liver, and we have reported the eventual emergence of tumors masquerading as hypernephroma and cutaneous mastocytomas (304). Most neurogenic tumors associated with the VIPoma syndrome have been found in children. Priapism has occurred, presumably resulting from a VIP-induced increase in blood flow to the corpora cavernosa. Catecholamines frequently are elevated; in patients with excess catecholamine secretion, flushing, increased sweating, and hypertension may occur. Hyperglycemia and hypercalcemia have not been noted in children. Plasma levels of PP are normal and have not been detected in VIP-producing ganglioneuroblastomas. Plasma PP levels nearly always are elevated if the tumor is in the pancreas. Thus, it was hoped that PP levels would distinguish pancreatic and nonpancreatic sources of VIP. However, three adults with neurogenic tumors and a 64-year-old woman with a VIPoma of the left kidney had high serum levels of PP (305). Excessive quantities of immunoreactive VIP and PP were found in the renal tumor tissue.

Biochemical Diagnosis

VIP is synthesized as the 170 amino acid precursor pre-pro VIP, which post-translationally is modified to yield the 28 amino acid VIP as well as peptide histidine and methionine (PHM) and other fragments (306). By definition, VIP levels are elevated in all patients with the VIPoma syndrome. (Assay available at Inter Science Institute-800-255-2873). Some of the non-VIP products of the precursor are secreted at higher levels than VIP itself, but, unfortunately, assays for these products are not commercially available and their clinical usefulness not established. False-positive elevations of VIP can be observed in patients with small bowel ischemia or severe low-flow states caused by diarrhea and secondary dehydration not associated with VIP-producing tumors (307-309).

VIP is not the only agent implicated in the diarrhea syndrome. Gastrin, secretin, glucagon, enteroglucagon, GIP, PP, VIP, thyrocalcitonin (TCT), prostaglandins, and peptide fragments of pre-pro VIP or any one of a number of combinations have been implicated as possible etiologic agents of the diarrhea syndrome (310). Bloom and colleagues reported 1,000 patients with various forms of diarrhea (308;311) Thirty-nine patients (3.9%) had greatly elevated levels of VIP, and, in each case, a tumor was found. In more than 50% of these patients, the tumor was successfully removed, the symptoms remitted, and the plasma levels of VIP returned to normal. Twelve patients had diarrhea secondary to TCT-producing tumors of the thyroid, 13 had carcinoma of the lung, 4 had a villous adenoma of the rectum, and 24 had carcinoid tumors. All 53 of these patients had normal plasma VIP levels. Eleven additional patients had classic clinical features of the VIPoma syndrome in whom VIP levels were normal and no tumor was found; they probably were secreting an unidentified humoral substance with the biologic properties of VIP.

Biochemical detection of VIP-secreting tumors necessitates a highly sensitive and specific VIP radioimmunoassay. The range of normal VIP concentration is 0 to 170 pg/mL, which is similar to that (0–190 pg/mL) found by others (289;296;312). Information gained from a single plasma VIP level may be misleading. The diagnosis of VIPoma in a patient with a good clinical history should not be excluded based on a single normal VIP because of vagaries in the assay. In addition, between periods of watery diarrhea, the VIPoma, unlike many endocrine tumors of the gut (e.g., insulinoma, gastrinoma), may not be actively secreting VIP; thus, a normal level creates a false sense of security and may delay a more vigorous search for the cause.

. In the series of 52 pancreatic cases reported by Long and colleagues,(293) most of the solitary tumors were 8 cm or greater in diameter. Most of these tumors are demonstrable using ultrasound or CT, but, occasionally, angiography or PTHVS are required (228). Somatostatin-receptor scintigraphy may be useful in identifying extrapancreatic VIPomas, particularly those in the sympathetic chain, or metastases (150). In summary, when confronted with severe chronic diarrhea, it must be established that the diarrhea is secretory in nature by fasting the patient for 48 hours and measuring stool volume. If diarrhea persists with fasting, VIP-producing tumors of the pancreas frequently are found, and plasma samples should be analyzed for VIP in these patients. If the VIP level is elevated, a VIP-secreting tumor (VIPoma) should be strongly suspected.

. In addition, a serum pancreatic polypeptide level should be determined simultaneously. If the tumor is located in the pancreas, this peptide almost invariably will be elevated. In children, catecholamine levels also should be obtained. If VIP levels are normal, screening for other causative agents, including gastrin, SP, somatostatin, PP, TCT, serotonin, glucagon, neuropeptide K, neurokinin A, peptide fragments of pre-pro VIP, and prostaglandins of the E series should be performed. Tumor localization should include CT, celiac, superior mesenteric , and renal angiography and, finally, PTHVS ^† Motility may be slightly increased secondary to direct effects of either intra-arterial or intraluminal VIP. Octreotide scanning may be useful, especially if metastases are being sought, but may not be quite as helpful in small primary lesions.

Treatment

The first step in the treatment of these patients is prompt replacement of fluid and electrolyte losses. Symptoms of severe electrolyte imbalance include cardiac arrhythmias, neuromuscular deficits, profound shock, and cardiovascular collapse. The fluid of choice is an isotonic electrolyte solution containing adequate sodium, potassium, and base.. If a tumor has been identified, complete surgical excision is the primary form of treatment. If the tumor cannot be removed completely, surgical debulking may have palliative benefit. In one series, surgical excision of the primary pancreatic tumor relieved all symptoms in 17 patients (27%) (313). Surgical removal of a ganglioneuroblastoma was successful in 7 of 10 patients. We do not advocate blind total pancreatectomy in patients who have diarrhea and in whom no tumor is demonstrable by angiography, CT, ultrasound, or PTHVS.

In the absence of finding a tumor, symptomatic therapy, not empiric surgery, is warranted. With malignant tumors, treatment with Sandostatin or chemotherapy must be considered Steroids have provided some symptomatic relief. A trial of prostaglandin synthesis inhibitors (e.g., indomethacin), phenothiazines, and lithium may be warranted (313). Octreotide has been used successfully in managing the diarrhea of VIPoma syndrome as well as that from the GEP tumors. Long-term octreotide treatment not only controls the diarrhea in these patients but also may cause arrest or regression of the tumor. Furthermore, we have seen spontaneous remission of watery diarrhea syndrome without establishing a cause, but we also have seen the eventual emergence of tumors in unusual sites, including the kidney and skin, only disclosed after careful follow-up for several years.